The present invention relates to platinum based drugs and methods of using such drugs and formulations thereof in antitumor therapy.
Some platinum based drugs are known to have useful antitumor activity. However, such drugs are also known to have various problems, such as toxicity or unsuitability for practical formulation and administration to patients. For example, cisplatin is one such drug with a significant level of antitumor activity, but which also exhibits significant nephrotoxicity and neurotoxicity.
Some of the present inventors previously developed certain lipophilic cisplatin analogs which can be entrapped in liposomes and which have the general structure: EQU DACH--Pt--R.sub.2
where DACH is diaminocyclohexane, and where R is a branched aliphatic carboxylato group of 5-10 carbons. One of the these complexes, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum-(II), entrapped in multilamellar vesicles composed of dimyristoyl phosphatidyl choline (DMPC) and dimyristoyl phosphatidyl glycerol (DMPG) at a 7:3 molar ratio (L-NDDP), has been the subject of a Phase I study in humans, and is now in two other clinical studies. Although information on the antitumor activity of L-NDDP in humans is not yet available due to its early stage of development, all preclinical information to date suggests that the concept of a lipophilic cisplatin analog entrapped in liposomes may be a therapeutic strategy of substantial use in the treatment of certain human malignancies.
However, L-NDDP has two major limitations. First, NDDP is a mixture of 15 to 20 isomers, thus making its full chemical characterization difficult, if not impossible. The second shortcoming relates to stability. NDDP undergoes chemical degradation into one or more active intermediates while entrapped in liposomes. The chemical degradation is essential for the complex to exert its antitumor activity in vivo, and is highly dependent on the presence and the relative amount of the phospholipid DMPG within the lipid bilayers. In other words, when liposomes devoid of DMPG are used, NDDP does not undergo degradation within the lipid bilayers and its in vivo antitumor activity is markedly reduced. But because of this degradation, L-NDDP does not meet standard chemical stability criteria for a pharmaceutical product.
Therefore, a need exists for improved formulations which will retain desirable antitumor activity while having improved chemical stability.